Method of manufacturing of 7-ethyl-10-hydroxycamptotecin

Abstract

The method of manufacturing of 7-ethyl-10-hydroxycamptothecin of formula I characterized in that 7-ethyl-1,2,6,7-tetrahydrocampotothecin of formula IV is oxidized with an oxidizing agent selected from the group coprising iodosobenzene, an ester of iodosobenzene, sodium periodate, potassium periodate, potassium peroxodisulfate and ammonium peroxodisulfate, in a solvent formed by a saturated aliphatic monocarboxylic acid containing 1 to 3 carbon atoms, and in the presence of water.

Description

FIELD OF THE INVENTION [0001] This invention relates to the method of manufacturing of 7-ethyl-10-hydroxycamptothecin of formula I which is used for manufacturing of cytostatically active irinotecan hydrochloride trihydrate, effective particularly in treatment of lung and rectum cancer. The cytostatic effect of irinotecan hydrochloride trihydrate is based on its ability to inhibit topoisomerase. BACKGROUND OF THE INVENTION [0002] So far, 7-ethyl-10-hydroxycamptothecin is usually prepared in two reaction steps. In the first reaction step, 7-ethylcamptothecin of formula II is oxidized with hydrogen peroxide in acetic acid under formation of 7-ethylcamptothecin 1-oxide of formula III which in the second reaction step is dissolved-in the solvent system dioxane-acetonitrile-water and the solution is irradiated with UV light in the presence of sulfuric acid to afford the desired 7-ethyl-10-hydroxycamptothecin (see U.S. Pat. No. 4,473,692 and U.S. Pat. No. 4,513,138 and Zhongguo Yaow...

AI Technical Summary

Benefits of technology

[0011] Preferred saturated aliphatic monocarboxylic acids are formic acid, acetic acid or trifluoroacetic acid, more preferred being acetic acid in an amount of 791 to 1187 mol, most preferably 890 to 1088 mol, per 1 mol of 1-ethylcamptothecin.

[0012] Preferred sulfur compound that partly deactivates the hydrogenation catalyst is dimethyl sulfoxide, preferably in an amount of 0.18 to 0.33 mol, more preferably in an amount of 0.23 to 0.28 mol, per 1 mol of 7-ethylcamptothecin.

[0013] Preferred hydrogenation catalyst is a noble metal, preferably platinum which is advantageously used on a carrier consisting of an activated carbon or aluminum oxide. Platinum is advantageously used in an amount of 0.018 to 0.027 mol, more advantageously in an amount of 0.020 to 0.025 mol, per 1 mol of 7-ethylcampto...

Problems solved by technology

However, this method of manufacturing of 7-ethyl-10-hydroxycamptothecin suffers from the fact that the oxidation of 7-ethylcamptothecin in the first reaction step requires relatively great amount of acetic acid (300 ml of acetic acid per 1 gram of 7-ethylcamptothecin).

This isolation procedure is demanding and affects very unfavourably the yield of 7-ethylcamptothecin 1-oxide.

Images